(Applicant's Abstract) The goals of this project are to identify genes that enhance susceptibility to the development of asthma and allergy. Asthma is a complex genetic trait that develops as a result of environmentally induced immune responses in genetically predisposed individuals. The proposed project applies genetic association analysis to identify atopy genes, utilizing an innovative, rapid, high-throughput genotyping methodology (Invader Assay) for assessing genetic variations (single nucleotide polymorphisms, SNPs). Using methods that we have employed extensively in the Stanford Human Genome Center (Co-Directed by the Project Co-Leader, David Cox) we will identify 5 common SNPs each in 50 candidate genes, primarily by examining sequence tagged sites (STSs) in coding and regulatory regions of these candidate genes. The candidate genes will be selected by considering their potential for affecting components of the allergic inflammatory response that underlies asthma, and will include candidate genes such as CNS-1, a newly identified locus control region of the IL-4 gene cluster on chromosome 5q31, Itk and IL-13 (both on chromosome 5q31), TGF-beta and others. We will enroll and characterize 1,000 atopic individuals and 1,000 nonatopic control subjects, and assess the frequency of candidate gene SNPs in DNA from these individuals using the high throughput Invader Assay, already established in the Stanford Genome Center. Our hypothesis is that while most SNPs are inconsequential and are present in low or equal frequency in atopic and nonatopic individuals, specific SNPs in genes that are critical in disease pathogenesis are common, and are present in higher frequency in atopic than in nonatopic populations. In this project we will screen 50 candidate genes for asthma/atopy, and identify mutations in 10- 16 genes that contribute to disease susceptibility. These studies, by identifying specific atopy genes, will greatly enhance our understanding of disease pathogenesis in asthma and allergy, and suggest novel therapeutic strategies for these diseases. In addition, these studies will provide the basis for identification of overall risk factors for atopy, which may lead to successful preventive treatments for asthma and allergy.